Focused Updates in Cerebrovascular Disease
Advances in Understanding Ischemic Stroke Physiology
and the Impact of Vasculopathy in Children
With Sickle Cell Disease
Kristin P. Guilliams, MD, MSCI; Melanie E. Fields, MD, MSCI; Michael M. Dowling, MD, PhD
See related article, p 230, 233, 240, 249 and 257
S ickle cell disease (SCD) is the most common hemoglobin-
opathy worldwide, with over 300 000 children born with
SCD each year.1 Neurological consequences of SCD include
ischemic and hemorrhagic strokes2 and cognitive deficits.3
SCD accounts for almost 1 out of 4 of all stroke-related hos-
pitalizations in black children.4 Historically, ischemic stroke
in SCD has been separated by symptomatology, including
“overt stroke,” referring to radiographic ischemia with associ-
ated neurological deficits detectable on a bedside examination
and “silent stroke” referring to radiographic ischemia without
focal neurological deficits, but associated with cognitive defi-
cits. However, this dichotomy is likely false, as the two can
be radiographically indistinguishable.5 Strokes may have life-
long devastating consequences, including limited educational
attainment and decreased quality of life in children.6,7 Sickle
cell anemia refers to the most severe SCD phenotypes, SS
Downloaded from http://ahajournals.org by on January 23, 2019
and Sβ0 thalassemia, which have the highest stroke incidence.
However, other SCD genotypes are also at risk for cerebral
ischemia, with up to 13% of hemoglobin SC children hav-
ing silent ischemia on screening magnetic resonance imaging
(MRI).2,8
Transcranial Doppler (TCD) screening to identify chil-
dren with SCD at highest stroke risk combined with primary
stroke prevention with chronic transfusion therapy (CTT)
revolutionized pediatric sickle cell stroke management in
the 1990s. Despite the dramatic reduction of “overt strokes”
through CTT shown in the STOP trial (Stroke Prevention Trial
in Sickle Cell Anemia), children with SCD remain at high risk
of stroke (Figure).2,9–21 Clinical and translational research in
the post-STOP era have increased our understanding of the
multifactorial complexity of stroke in children with SCD
(Table 1). Recent work has demonstrated how components of
the cerebral metabolic rate of oxygen utilization contribute to
ischemia in SCD. Cerebral metabolic rate of oxygen utiliza-
tion is the product of cerebral blood flow (CBF), arterial ox-
ygen content (CaO2). and oxygen extraction fraction (OEF).
CBF and CaO2 comprise cerebral oxygen delivery, and OEF
Received April 25, 2018; final revision received November 20, 2018; accepted November 28, 2018.
From the Department of Neurology (K.P.G.) and Department of Pediatrics (K.P.G., M.E.F.), Washington University School of Medicine, St Louis, MO;
and Department of Pediatrics and Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas (M.M.D.).
Correspondence to Kristin P. Guilliams, MD, MSCI, Washington University School of Medicine, 660 S Euclid Ave Box 8111, St Louis, MO 63110.
Email kristinguilliams@wustl.edu
(Stroke. 2019;50:00-00. DOI: 10.1161/STROKEAHA.118.020482.)
© 2019 American Heart Association, Inc.
Stroke is available at https://www.ahajournals.org/journal/str
1
quantifies the transfer of available oxygen supply into the
brain tissue. Ischemia occurs when cerebral metabolic rate of
oxygen utilization does not meet the metabolic demands and
falls below the threshold of tissue viability.26 Here, we will
review advances in causal pathways of ischemic stroke and
therapy options.
Oxygen Content
Decreased CaO2 in SCD can result from anemia, hypoxia,
and the altered oxygen delivery of hemoglobin (Hb) S. Severe
anemia is associated with acute cerebral ischemia in children
with and without SCD.27 CaO2 depends not only on the amount
of hemoglobin (lowered by hemolysis or red blood cell seques-
tration), but also the percent saturated, commonly measured by
pulse oximetry (SpO2). Oxygen saturation may be transiently
or persistently decreased in SCD; possible mechanisms include
rightward shifting of the oxygen desaturation curve,28 noc-
turnal desaturation during sleep,29,30 presence of a right-to-left
shunt at the cardiac or pulmonary level,31 or lung pathology,
such as acute chest syndrome. Lower steady-state daytime
SpO2 increases risk of infarction, with the odds ratio for “overt
stroke” increasing by 1.32 for each 1% decrease in pulse ox-
imetry value.32 Lower SpO2 is also associated with increased
blood flow velocity, as measured by TCD,33 and microstruc-
tural white matter abnormalities.34 Upper airway obstruction
and obstructive sleep apnea correlate with increased risk of
neurological complications.35 Adenotonsillectomy improves
TCD velocities36 and is cost-effective in SCD because of
decreased visits for cerebral ischemic events.37
Chronic Transfusion Therapy
A direct way to increase CaO2 is through red cell transfusion,
which increases total hemoglobin and decreases HbS%. Early
studies of CTT, with dual goals of transfusing to keep Hb >10
gm/dL and HbS <30%, demonstrated dramatic secondary
stroke prevention.38 Subsequent studies have used variations
of these initial goals, and current guidelines simplify recom-
mendations to keep HbS <30% for primary and secondary
DOI: 10.1161/STROKEAHA.118.020482
 2  Stroke  February 2019

Figure.  Stroke event rates as reported in the

literature. CTT indicates chronic transfusion
therapy; SCD, sickle cell disease; and TCD,
transcranial Doppler.

stroke prevention, as this has been most commonly used in tri-
als. However, no studies have compared outcomes of differing
transfusion goals.39 CTT is associated with alloimmunization,
transfusion reactions, iron overload, increased thrombotic
risk with central line placement, and increased mortality.40,41
Careful monitoring is required to minimize complications.
Furthermore, CTT has academic and socioeconomic conse-
quences because of missed school and work days.
Multiple studies have sought to determine whether CTT
is only needed for a high-risk period, or if patients may be

Table 1.  Major Randomized Clinical Trials of Stroke in Sickle Cell Disease

Primary
Trial Population Screened Enrollment Intervention Primary End Point Results Conclusion
STOP9 1934 children ages 130 children with TCD Randomized to receive Clinical stroke: 1 stroke in CTT group; 92% risk reduction
2–16 y with HbSS or velocities >200 cm/s standard care or CTT cerebral infarction 11 strokes in standard of clinical stroke with
HbSβ0 thalassemia, on 2 TCD studies to target HbS <30% and intracranial care CTT.
Downloaded from http://ahajournals.org by on January 23, 2019

screened with TCD hemorrhage

STOP-222 Children receiving 79 children on CTT Randomized to Clinical stroke or 14 reversion of CTT cannot be safely
CTT for primary stroke who had 2 normal TCD continue or stop CTT reversion of TCD TCD velocity 2 stopped without
prevention for >30 m measurements velocity >200 cm/s clinical strokes in increase in stroke risk
nontransfused group;
0 events in transfused
groups
SWiTCH23 202 children on CTT 134 children with prior Randomized to CTT+ Composite end point of 7 strokes in HU arm, Cannot safely switch
>18 m with iron stroke on CTT with chelation or HU+ stroke recurrence and no difference in liver from CTT to HU for
overload liver iron content ≥5 phlebotomy liver iron content iron content secondary stroke
mg/g dry weight prevention
TWiTCH24 159 children receiving 121 children on CTT Randomized to 24 m TCD velocity TCD velocities met May transition children
CTT for primary stroke with adequately continue transfusions unchanged within noninferiority margins; on CTT for TCD to HU
prevention ≥12 m measured TCD or start HU and noninferiority margin no new strokes, but after 12 m of CTT
velocities phlebotomy protocol TIAs occurred in each
group
SIT17 1074 children ages 196 children with Randomized to Infarct recurrence, CTT group: 1 clinical CTT can reduce infarct
5–15 screened with silent infarct observation only (no including enlargement stroke and 5 new silent recurrence compared
MRI for silent infarct HU) or CTT to maintain by ≥3 mm or infarcts; with no therapy
Hb >9.0 g/dL and HbS hemorrhage control group: 7
<30% clinical strokes, 7 new
silent infarcts, 2 TIAs
SCATE25 1234 children ages 115 identified; Randomized to Conversion to Terminated early Underpowered for
2–11 y screened with 38 children with observation or to abnormal TCD velocity because of slow primary analysis,
TCD conditional TCD receive HU escalated in any vessel enrollment; TCD but HU may prevent
velocity within 3 m to maximum tolerated conversion: 47% conditional TCD
enrolled dose observation group, 9% conversion
HU group
CTT indicates chronic transfusion therapy; Hb, hemoglobin; HU, hydroxyurea; MRI, magnetic resonance imaging; SCA, sickle cell anemia; SCATE, Sparing Conversion to
Abnormal TCD Elevation; SIT, Silent Infarct Transfusion; STOP, Stroke Prevention Trial in Sickle Cell Anemia; STOP-2, Optimizing Primary Stroke Prevention in SCA; SWiTCH,
Stroke With Transfusion Changing to Hydroxyurea; TCD, transcranial Doppler; TIA, transient ischemic attack; TWiTCH, TCD With Transfusions Changing to Hydroxyurea.
 Guilliams et al   Stroke in Pediatric Sickle Cell Disease   3
transitioned to other stroke prevention strategies, thereby lim-
iting morbidity. STOP-2 (Optimizing Primary Stroke Prevention
in SCA) randomized children to discontinue CTT when TCD
normalized but was terminated early because of non-CTT co-
hort reverting to high-risk TCD velocities or experiencing new
strokes.22 The SWiTCH trial (Stroke With Transfusions Changing
to Hydroxyurea) sought to determine whether hydroxyurea
paired with phlebotomy could be as effective as CTT paired with
chelation in children on stable CTT. The composite primary end
point was secondary stroke recurrence rate and quantitative liver
iron overload. The study was closed at interim analysis because
of an inability to meet the end point; there was no difference in
liver iron concentration between the 2 cohorts, and 7 new strokes
occurred within the hydroxyurea arm.23 Follow-up imaging anal-
yses from the SWiTCH trial found a high incidence of vasculopa-
thy (58% and 46% on the left and right, respectively). Of note, all
7 participants that had a stroke during the trial had vasculopathy.42
Lifelong CTT remains the only proven strategy for secondary
“overt stroke” prevention. Although CTT is the most effective
intervention for secondary stroke prevention, up to 45% of chil-
dren on CTT may still experience ischemic events.16 Children
with vasculopathy and without any clear physiological stressor
(ie, acute chest, acute anemia) proximal to the initial stroke seem
to have the highest recurrence rate.16,18
The SIT trial (Silent Cerebral Infarct Multi-Center Clinical
Trial aka Silent Infarct Transfusion), sought to extrapolate the
benefits of CTT in the “overt stroke” population to the “silent
stroke” population.17 Silent infarcts also carry neurological mor-
bidity, demonstrate a high rate of recurrence, and increase risk
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of “overt stroke.”43 Of the 1074 children screened, silent infarcts
were found in 379 (35%), and 196 were randomized to transfu-
sions or standard care. The study demonstrated a 58% relative
risk reduction in infarct recurrence, but with a number needed
to treat NNT of 13 over 3 years to prevent one infarct, the per-
ceived risk-benefit may differ among families.17 Although CTT
is not currently widespread standard of care for secondary
“silent stroke” prevention, these results warrant in-depth dis-
cussions with families to reach shared decision making in bal-
ancing the risks of CTT with the risks of further infarcts.
Hydroxyurea
Hydroxyurea is a ribonucleotide reductase inhibitor that increases
hemoglobin, and thereby CaO2, via an increase in hemoglobin F
production, in addition to counteracting the downstream effects of
sickling and hemolysis by decreasing white blood cell and platelet
counts and increasing nitric oxide.44 In 1995, hydroxyurea was first
shown to be clinically effective in adults with a decrease in pain-
ful events, acute chest syndrome, red blood cell transfusions, and
mortality.45 In 1998, the Food and Drug Administration approved
its use in adults with SCD. The HUG-KIDS Study (Predicting
Early Mortality From Ischemic Stroke) provided Phase I/II data in
children shortly thereafter in 1999.46 This led to recommendations
for all children with SCA to be offered hydroxyurea therapy by 9
months of age in the National Heart Lung Blood Institute 2014
Evidence-Based Report39 and Food and Drug Administration ap-
proval for children with SCD in 2017.
The role of hydroxyurea in primary stroke prevention war-
rants further investigation, but the available data are promising
in specific clinical scenarios. The BABY HUG trial (Pediatric
Hydroxyurea Phase III Clinical Trial), the first randomized,
double-blind trial of hydroxyurea in children with SCD, found
that the increase in TCD velocities from study entry to exit
was significantly lower in the cohort of children receiving
hydroxyurea therapy when compared with those receiving
placebo.47 Data from Nigeria suggests that hydroxyurea can
be used for primary stroke prevention in patients with el-
evated TCD velocities ≥170 cm/s living in environments
lacking resources for CTT.48 Even though the phase III mul-
ticenter, international SCATE trial (Sparing Conversion to
Abnormal TCD Elevation) closed early because of slow ac-
crual, the data suggests that hydroxyurea can prevent conver-
sion to an abnormal TCD, potentially avoiding the need for
CTT.25 A retrospective study also showed a higher percentage
of TCD velocity improvement in those receiving hydroxy-
urea compared with those without intervention.49 For patients
on CTT for primary stroke prophylaxis because of elevated
TCDs, results of the phase 3, noninferiority TWiTCH trial
(TCD With Transfusions Changing to Hydroxyurea) found
that in children who had received at least 12 months of CTT,
hydroxyurea maintained equivalent TCD as they had achieved
on CTT. Of note, patients with vasculopathy were excluded
from the TWiTCH trial; hence, data does not currently sup-
port the use of hydroxyurea for primary stroke prevention in
the subgroup of SCD patients with vasculopathy.24 As noted
above, the SWiTCH study demonstrated that hydroxyurea
cannot be recommended for secondary “overt stroke” preven-
tion.23 The role of hydroxyurea for SCI prevention remains
unclear. Participants receiving hydroxyurea therapy in the
prospective, observational HUSTLE (Hydroxyurea Study of
Long-Term Effects) did not develop new or enlarging SCIs
at the rate one would expect per the natural history of the di-
sease.50 Comparison of HUSTLE to SIT data suggest hydroxy-
urea may be effective for recurrent SCI prevention51
Expanding Hydroxyurea Indications
for Stroke Prevention
With TWiTCH demonstrating a subset of children on CTT
who may safely transition to hydroxyurea without apparent
increased risk, future work may include identifying other CTT
populations, such as those without vasculopathy who had an
acute concurrent medical event before their stroke,18 who may
also be able to successfully transition off CTT to hydroxyurea.
Safe alternatives to CTT are needed because the majority of
the world’s SCD population lives in low-income countries,1
and, therefore, implementation of lifelong CTT may exceed
locally available resources.
Recent studies have focused on translating knowledge
gained from high-resource countries to stroke prevention
strategies in Africa. Hydroxyurea has been demonstrated to
lower TCD in an African cohort,48 but maximal dosing of
hydroxyurea requires resources for monitoring dosing and
toxicity.46 Currently multiple large trials (REACH [Realizing
Effectiveness Across Continents With Hydroxyurea], SPRING
[Primary Prevention of Stroke in Children With SCD in Sub-
Saharan Africa II], NOHARM [Novel Use of Hydroxyurea
in an African Region With Malaria], SACRED: [Stroke
 4  Stroke  February 2019
Avoidance for Children in Republica Dominicana], EXTEND
[Expanding Treatment for Existing Neurological Disease])
are underway to determine optimal hydroxyurea management
in SCD worldwide (www.clinicaltrials.gov).52 Several trials
have demonstrated feasibility and enhancement of local re-
sources and all hold promise to significantly advance care for
people with SCD.53,54
Cerebral Blood Flow
The relationship between CBF and ischemic stroke in SCD
has long been recognized but remains incompletely under-
stood. Quantitative CBF is the total volume of blood measured
per minute, normalized to 100 g of brain tissue. Ford et al55 re-
cently demonstrated that regions of lowest CBF correspond to
areas of highest frequency of silent cerebral infarct in children
with SCD. Adams et al56 demonstrated correlation between
high TCD values and “overt stroke” risk. TCD measures only
the speed of blood passing through the major cerebral arteries,
and values are typically reported as centimeters per second.
CBF and TCD do not directly correlate without conversion of
the TCD velocity to CBF units, based on arterial size and es-
timation of tissue weight supplied by the artery, both of which
require MRI measurements.57
TCDs are portable and noninvasive, but limitations include
high operator-dependence, inability to detect velocities in all
patients, particularly those with poor bone windows, a low
specificity for stroke,56 and they do not predict silent ischemia.
TCD does not have direct correlation with underlying vascular
abnormalities, but stenosis may influence TCD values by ei-
Downloaded from http://ahajournals.org by on January 23, 2019
ther raising or significantly lowering velocities.58 Hematocrit
and SpO2 (ie, CaO2), as well as age, have been correlated with
TCD values.33 Of note, initial studies used nonimaging TCDs,
and imaging TCD systems provide values ≈10% lower than
nonimaging, so thresholds should be adjusted based upon the
system.59
Multiple MRI modalities are capable of measuring CBF
with various pros and cons to each technique.60 Cerebral in-
ternal carotid artery and middle cerebral artery luminal area
are increased in SCD,61 and CBF is elevated in children with
SCD compared with controls.62,63 Vasodilatory autoregula-
tion of the cerebral vasculature allows for the brain to titrate
blood flow based on metabolic demand and arterial oxygen
supply. CBF values inversely correlate with hemoglobin and
CaO2,62,64,65 and transfusions decrease CBF. Severe anemia
may push cerebral vasculature to maximal compensation,
such that the drive to maintain oxygen delivery overrides the
vasculature’s usual sensitivity to other factors, such as carbon
dioxide. Kosinski et al66 recently demonstrated that the cere-
bral reactivity reserve is lost with severe anemia of SCD but
can be restored with the increased Hb from transfusion.
Vasculopathy
The field has been plagued by inconsistent use of the term
vasculopathy in the literature, which creates challenges for
direct comparisons of studies (Table 2). Future endeavors
should work to unify definitions, possibly with non-SCD
pediatric arteriopathy scales.71 Despite the wide array of
definitions, vasculopathy is consistently associated with an
increased risk of ischemia in SCD. Presumably through lim-
itation of CBF, vasculopathy is associated with ischemia,68
stroke recurrence,16,23,42 and distal atrophy.70 Autopsy studies
demonstrate intimal hyperplasia and mural thrombi.72,73 The
degree of anemia may contribute chronic exposure to shear
stress, and through improved total hemoglobin, hydroxyurea
may slow or potentially prevent development of vasculopathy.
Vasculopathy occurs in 12% to 23% of children with SCD14,67;
reasons for incomplete penetrance remain poorly understood.
Genetic factors almost certainly play a role as well, including
glucose-6-phosphate dehydrogenase (G6PD),68 although
G6PD has not been found to have an association with overall
stroke risk.74,75
Moyamoya angiopathy is a severe form of vasculopathy
with progressive occlusion of one or both internal carotid
arteries commonly associated with collateral vessel growth,
which can occur in children with and without SCD. Surgical
revascularization provides alternative blood supply through
either direct bypass or, more commonly in children, indi-
rect procedures which improve CBF and decrease ischemic
events in children without SCD.76,77 Similarly, children with
SCD, may also have decreased ischemic events after indirect
revascularization surgery, regardless of the method used, with
several studies reporting zero further ischemic events in the
postsurgery follow-up period.78–81 Although Winstead et al82
reported that 3 out of 7 SCD children with moyamoya who
underwent surgery did not have successful revascularization
with flow through the graft, an important detail is that 2 chil-
dren were managed on concomitant CTT and hydroxyurea,
although details of the timing of hydroxyurea and revascu-
larization surgery are not provided. As hydroxyurea inhibits
angiogenesis,83,84 it is imperative that these 2 stroke reduction
management strategies not be used simultaneously in children
with SCD. This must also be remembered as hydroxyurea is
commonly used in preparation for stem-cell transplantation
(SCT), warranting careful multidisciplinary discussion about
timing of for stem-cell transplantation postrevascularization.
At our institutions, we attempt to hold hydroxyurea (and thus
for stem-cell transplantation) for 6 to 12 months postrevascu-
larization to maximize surgical benefit.
Oxygen Extraction
The OEF reflects the amount of oxygen that diffuses from
the bloodstream into tissue. An increased OEF, reflective of
a decrease of oxygen content or CBF, or increased cerebral
metabolic rate of oxygen utilization, heralds stroke risk in
non-SCD adults.85 Historically, OEF was measured with posi-
tron emission tomography, but more recent techniques enable
measurement with MRI, thus sparing radiation exposure.86,87
MRI techniques have demonstrated an increase in global
OEF in SCD,88,89 as well as regionally elevated OEF in the
borderzone region of children with SCD,63 and decreases in
the volume of regions with highest OEF with transfusion.90
Work is needed to determine whether MRI-measured OEF
may serve as a screening option to predict ischemia in chil-
dren with SCD, and even more work is needed to translate
OEF into clinical practice to optimize CTT, such as decreas-
ing transfusion frequency or individualizing HbS% goal, if
 Guilliams et al   Stroke in Pediatric Sickle Cell Disease   5

Table 2.  Study Definitions of Vasculopathy or Arteriopathy in SCD

Assessment
Year First Author Parent Study/Cohort Modality Vasculopathy Definition Used in Study Prevalence Reported
2003 Steen 67
Cooperative Study of Sickle MRA Stenosis, occlusion of any vessel, or subjective 102/185 (55%) SCD
Cell Disease clinical assessment of vessel tortuosity
2011 Hulbert16 Neuroheme consortium MRA >50% stenosis or occlusion of first segments of 25/35 (71%) SCD
ICA, ACA, MCA, or PCA
2012 Thangarajh68 SIT trial MRA >50% stenosis or occlusion of CoW vessels 53/516 (10%) SCA
(similar to Hulbert et al16)
2014 Helton42 SWiTCH MRA Grading system (0–6) based on degree of 104/150 (69%) SCA with “overt
stenosis (estimated by percent of occlusion) and stroke”
number of involved segments
2016 Joly69 Lyon cohort TCD/MRI “Overt stroke,” silent infarct, abnormal TCD 22/121 (18%) SCA
2015 Bernaudin 14
Creteil sickle cell anemia MRA >20% decrease in lumen of MCA, ACA, 24/189 (13%) intracranial
newborn cohort intracranial ICA, or extracranial ICA 35/189 (19%) extracranial SCA
2016 Sommet19 Robert Debre sickle cell TCD/MRA Either 2 abnormal TCDs, 2 high conditional 59/375 (16%) SCA
disease newborn cohort TCDs+MRA with moderate to severe stenosis,
or any “overt stroke”
2016 Nottage50 HUSTLE MRA Scoring system of degree of stenosis (similar to 0/50 (0%) SCA on hydroxyurea
Helton et al42)
2017 Guilliams70 Washington University MRA Any vascular narrowing within distal ICA or 23/84 (27%) SCD with overt/“silent
cohort proximal ACA or MCA stroke”
2017 Dlamini29 East London cohort MRA Grading system (0–3) based on signal 30/47 (64%) SCD
attenuation/loss of CoW vessels
Notation includes definitions based on previously reported methodology. ACA indicates anterior cerebral artery; CoW, circle of Willis; HUSTLE, Hydroxyurea Study of
Long-Term Effects; ICA, internal carotid artery; MCA, middle cerebral artery; MRA, magnetic resonance arteriography; P
CA, posterior cerebral artery; SCA, Sickle cell anemia; SCD, Sickle Cell Disease; SIT, Silent Infarct Transfusion; and SWiTCH, Stroke With Transfusions Changing to
Hydroxyurea.
Downloaded from http://ahajournals.org by on January 23, 2019

OEF successfully predicts stroke risk. However, recent studies Disclosures

and broad interest in the field suggests OEF holds promise for
advancing precision medicine in SCD.91
Conclusions
Stroke in SCD is multifactorial and complex, and there have
been significant physiological and clinical advances in recent
years. Future directions will include recognition of different
causes of ischemic stroke and efforts toward decreasing the
transfusion burden, either through identifying further children
who may safely transition to other therapies or through indi-
vidualization of CTT. An increased appreciation for the role
of vasculopathy should lead to more investigation of thera-
pies commonly used in other populations with vasculopathy,
including antiplatelet agents and revascularization. Primary
and secondary stroke prevention in SCD has greatly improved
over the past decades, but further work is needed to continue
to reduce stroke in SCD around the world.
Acknowledgments
The authors thank Andria L. Ford, MD, for critical review of the
manuscript.
Sources of Funding
This study is funded by National Institutes of Health: K23NS099472
(Dr Guilliams), K23HL136904 (Dr Fields), and Child Neurology
Foundation (Dr Guilliams)
Dr Dowling serves on the Data Safety and Monitoring Board for
the SPRING trial (Primary Prevention of Stroke in Children with
SCD in Sub-Saharan Africa II; NCT 02560935) and served as a
member of the Neurology Committee for the SIT trial (Silent
Infarct Transfusion; U01 NS042804) and TWiTCH (TCD With
Transfusions Changing to Hydroxyurea; 7RO1 HL095647-03), a
site neurologist for SWiTCH (Stroke with Transfusion Changing to
Hydroxyurea; 5U01 HL078787-05) and BABY HUG trial (Pediatric
Hydroxyurea Phase III Clinical Trial; N01-HB07159), and principal
investigator for the Doris Duke Charitable Foundation PFAST study
(Patent Foramen Ovale and Stroke in Sickle Cell Disease). The
other authors report no conflicts.
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KEY WORDS: anemia ◼ cerebrovascular circulation ◼ hemolysis ◼ hydroxyurea
◼ oxygen consumption ◼ stroke